Disease relapse is a leading etiology of morbidity and mortality for patients with non-Hodgkin lymphoma (NHL) and autologous hematopoietic stem cell transplant following a myeloablative preparative regimen (auto-HSCT) can salvage only a subset of these patients. This Lymphoma SPORE Project 1 renewal resubmission seeks to develop targeted cellular immunotherapy capable of eradicating lymphoma posttransplant minimal residual disease (MRD) using CD19-specific T cell adoptive immunotherapy (AIT). Over the last funding cycle, we developed a genetic engineering approach to equip T cells with the ability to recognize and lyse tumor cells of B-cell lineage NHL using chimeric antigen receptors (CARs) specific for CD19 and initiated a first-in-human pilot clinical trial. Our initial clinical experience revealed a significant obstacle to achieving robust therapeutic activity; namely, that infused T cells survived only transiently in the tumor-bearing recipient. To address this critical issue, we elected to study the fate of adoptively transferred T cells using a non-human primate model that closely recapitulates clinical therapy in humans. These studies have revealed a key insight- that a rare population of T cells present in the circulation, the central memory T cell (TCM). is capable of high-level sustained engraftment following adoptive transfer. Accordingly, we have reconfigured our clinical T cell production platform to immunomagnetically purify CDS* TCM from peripheral blood mononuclear cell preparations. These CDS* TCM then undergo polyclonal activation, lentiviral vector transduction to express a CD19-specific scFvFc:^ CAR, and are expanded over a brief 21-day interval in IL- 2/IL-15 prior to cryopreservation. The first specific aim of the project seeks to demonstrate that CD19RCAR^ CDS* TcM-derived effector cells from NHL patients are phenotypically and functionally similar to those derived from healthy donors. The second aim seeks to define the maximum tolerated dose (MTD) of CD19R-CAR*CD8* TcM-derived effector cells when infused shortly following auto-HSCT (Day +2) when patients with recurrent diffuse large cell lymphoma (DLCL) have minimal disease burdens and are profoundly lymphopenic from the transplant myeloablative preparative regimen. The third specific aim seeks to determine the magnitude and duration of persistence of transferred T cells in treated patients, the ability of transferred effector cells to revert to TMEM and populate memory T cell niches, and the anti-CD19 effector functioning of these cells in patients as determined by tracking the kinetics of CD19* B cell reconstitution. Lastly, we will seek to demonstrate the exportability of the approach by opening the trial to patient accrual both at the FHCRC in Seattle as well as City of Hope. Each of these Specific Aims focuses on key translational research objectives essential for moving the field of lymphoma AIT forward, including the conduct of a first-in-human trial using central memory T cell adoptive therapy. As such. Project 1 is fully aligned with the SPORE mandate for innovative translational research.